WO2018108238A1

WO2018108238A1 - Combination product that helps relax and fall asleep

Info

Publication number: WO2018108238A1
Application number: PCT/EP2016/080654
Authority: WO
Inventors: Tiphaine BRICOUT; Marilyn GENTILHOMME
Original assignee: Urgo Recherche Innovation Et Developpement; Hcp Healthcare Asia Pte Ltd
Priority date: 2016-12-12
Filing date: 2016-12-12
Publication date: 2018-06-21
Also published as: EP3551206A1

Abstract

The invention relates to a combination product comprising, as active substances, at least valerian, Passiflora, Rhodiola and hawthorn or a bioequivalent compound of same for helping with stress management, relaxation and/or falling asleep. The invention further relates to the use of a combination product as defined above for the treatment or prevention of stress and sleep disorders.

Description

Combination product to help with relaxation and falling asleep

TECHNICAL AREA

The subject of the present invention is a combination product comprising, as active substances, at least valerian, passionflower, rhodiola and hawthorn or a bioequivalent compound of the latter to aid relaxation and / or to fall asleep. The invention finally relates to the use of a combination product as previously defined for the treatment or prevention of stress and somnipathies.

BACKGROUND

Stress is a normal reaction of the body to environmental stresses. If it is temporary the stress can be positive, but if it lasts too long it can play on the health.

The origin of stress can be multiple, it is due to what are called stressors or "stressors". It is a feeling of normal physical or emotional tension. There are two types of stress:

Acute stress that quickly disappears. It is stress that, for example, helps the body to increase its performance or adapt to a new situation.

Chronic stress that lasts for a while. It is due to deeper problems. Any stress lasting several weeks or months is called chronic stress.

The body reacts to stress through the release of hormones that will play on the brain, muscles and heartbeat. In the short term, these reactions are beneficial to the body and protect it because they allow humans to manage and overcome the stress situation. On the other hand, if the stress persists, the human body remains perpetually in a state of alert despite the absence of danger.

Continuous release of hormones and activation of the brain, muscles, and heart can lead to health risks such as high blood pressure, heart problems, anxiety, depression, or skin problems. A sleep disorder (somnipathy) is a disorder related to an individual's sleep habits. Some sleep disorders are serious enough to interfere with physical, mental and emotional functioning. A test commonly used for sleep disorders is polysomnography. Sleep dysfunction can be caused by a variety of problems, from grinding of teeth (bruxism) to night terrors. When an individual has difficulty falling asleep without apparent cause, it is insomnia. In addition, sleep disorders can lead the individual to sleep enormously, a situation known as hypersomnia. Other conditions of the sleep disorder may be related to substantial abuse.

Sleep disorders include:

- primary insomnia - chronic difficulty falling asleep and / or maintaining sleep when no other symptomatic cause can be perceived;

- bruxism, creaking or involuntary clanging of the teeth during sleep; -Sleep phase delay syndrome, inability to fall asleep or to wake up for socially acceptable hours but not causing any problems in sleep maintenance, circadian rhythm disorder (similar symptom - hypernycthemeral syndrome);

hypopnoea, respiratory or cardiac abnormality during sleep;

-narcolepsy, sudden sleep often spontaneous at any time of the day; cataplexy, sudden weakness of the motor muscles that may result in a fall on the ground;

- nocturnal terror, pavor nocturnus, nocturnal disorder characterized by strong fear and anxiety;

sleepwalking, an activity that is physically and unconsciously engaged during sleep; Somniphobia, afraid to sleep; sleep apnea Following the evolution of knowledge about sleep in the twentieth century, including the discovery of hypnology and sleep apnea, the medical importance of sleep is recognized. The clinical community is taking a closer look at sleep disorders, such as sleep apnea, and the role and quality of sleep under different conditions. During the 1970s in the United States, clinics and laboratories devoted themselves to the study of sleep accompanied by its troubles.

The impact of sleep disorders on the lives of individuals can be very important: a study in 2014 found that sleep perceived as being of poor quality is associated with an increased risk of suicide in the elderly ( mean age in the study, 74.9 years plus or minus 5.6 years).

Sleep medicine is now adapted in internal medicine, family medicine, pediatrics, otolaryngology, psychiatry and neurology.

The present invention relates to a composition for assisting stress management, relaxation and sleep in adults or children, preferably in adults. Indeed, a study published in Paediatrica (vol 14 no. 3 2003) takes stock of children's sleep disorders. Up to 25% of small children and almost 50% of school-aged children have sleep disorders that have lasted for at least 6 months. The prevalence is 33% for adolescents. Hedger Archbold et al. have differentiated these disorders. Some sleep disorders are more common at a certain age and related to particular situations, others can occur at any age (for example: sleep apnea syndrome, sleep-related epilepsies. is not only a problem for parents Disrupted sleep also entails risks for the cognitive development of the child with the occurrence of behavioral disorders As for adults, it seems that there is an association between obstructive apnea sleep and a higher prevalence of metabolic syndrome in children and adolescents.

The duration and organization of sleep are subject to changes during development. Basic knowledge helps distinguish true sleep disorders from variations in the norm. As an indication the approximate values of sleep duration in 24 hours are: 16 hours for the newborn term, 13 hours for the child of 2 years, 11 hours to 5 years, 10 hours to 9 years and about 9 hours for a teenager 14 years. Young adults still need about 8 hours, a fact often forgotten. The variability of these values is quite important and corresponds to the distribution of genetic traits in the population. Individual sleep needs are more easily established during weekends and holidays when the body is allowed to sleep for as long as needed.

During the night, three states are observed: wakefulness, REM sleep (rapid eye movement sleep) and non-REM sleep (slow sleep). A sleep cycle includes a passage through the three states. In deep sleep can come different parasomnias (non-REM parasomnias): for example nocturnal terrors of small children, which are replaced by somnambulism at the bigger child. Since sleep cycles with deep phases occur in the first half of the night, it is usual to observe these parasomnias during the first hours after

I fall asleep.

There are on the market a number of products to overcome the problems of falling asleep or relaxation. Among these products, there may be mentioned, for example, the products marketed by Sanofi under the trade name Nova Nuit Sommeil made from passionflower, melatonin, California poppy, lemon balm and vitamin B6 or the product Somdor + Melatonin from Granions which contains melatonin, an extract of lemon balm, hawthorn, passionflower, hops and valerian. None of the products proposed contains the association object of the present invention.

These products, although containing valerian in combination with passionflower and hawthorn, do not provide complete satisfaction in terms of appeasement, relaxation and / or help with falling asleep. The combination product of the present invention provides a soothing effect to facilitate falling asleep, especially for children, and help them to naturally recover a restful sleep, without nocturnal awakening. The product according to the present invention has no side effects or addiction. The combination product of the present invention helps to help you fall asleep, soothes, relaxes and helps maintain a healthy sleep. It also contributes to the proper functioning of the nervous system. The product according to the present invention also has the advantage of preferably containing no allergen and preferably being lactose or gluten-free.

The product of the present invention has a galenic adapted to the child and the adult, preferably in the form of a capsule. SUMMARY OF THE INVENTION

The present invention relates to a combination product comprising as active substances at least:

(i) valerian,

(ii) passionflower, (iii) rhodiola, and

(iv) hawthorn or a bioequivalent compound of valerian, passionflower, rhodiola and / or hawthorn to assist with stress management, relaxation and / or sleep.

The present invention also relates to a combination product comprising as active substances at least:

(i) valerian,

(ii) passionflower,

(iii) rhodiola, and

(iv) hawthorn or a bioequivalent compound of valerian, passionflower, rhodiola and / or hawthorn for use in the treatment or prevention of stress and somnipathy.

In certain embodiments, the combination product according to the invention comprises, in addition to valerian, passionflower, rhodiola and / or hawthorn, as active substances: (i) Plants or extracts of plants, such as, for example, orange blossom, lavender, marjoram, hops, gentian and / or lemon balm,

(ii) Vitamins and minerals, such as for example vitamin D, B vitamins, such as vitamin B6, magnesium and / or calcium

(iii) Amino acids or amino acid derivatives, such as, for example, tryptophan

In certain embodiments, the combination product of the invention is characterized in that valerian, passionflower, rhodiola and hawthorn are in the form of plant extracts and are administered at a daily dose of 500 mg / day, preferably 100 to 300 mg / day of valerian extracts of 5 to 200 mg / day, preferably 50 to 150 mg / day of passionflower extracts of 20 to 200 mg / day, preferably 50 to 150 mg / day of rhodiola extracts of 5 to 100 mg / day, preferably 20 to 80 mg / day of hawthorn extracts

In some embodiments of the invention, the combination product according to the invention may be in the form of a single (or combined) composition containing at least as active substances:

(i) valerian,

(ii) passionflower,

(iii) rhodiola, and

(iv) hawthorn in a physiologically acceptable medium.

In some embodiments of the invention, the combination product according to the invention may be in the form of a single composition containing at least as active substances: from 50 to 500 mg, preferably 100 to 300 mg valerian extracts of 5 to 200 mg, preferably 50 to 150 mg of passionflower extracts from 20 to 200 mg, preferably 50 to 150 mg of rhodiola extracts of 5 to 100 mg, preferably 20 to 80 mg of hawthorn extracts

According to a particular embodiment of the invention, the combination product is characterized in that the active ingredients (i), (ii), (iii), (iv) or a bioequivalent compound thereof are in a medium adapted to oral administration. Preferably, the combination product is in the form of powder or a capsule containing said powder.

When used for the therapeutic treatment of sleep disorders, the combination product according to the present invention is especially intended for adults or children.

Valerian, passionflower, rhodiola, and hawthorn may be present as ingredients (i), (ii), (iii) or (iv) in a combination product of the invention in more or less form. purified, especially in the form of a plant extract.

The various embodiments of the invention are particularly described in the detailed description below. These embodiments may be taken separately or in combination with each other.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the applicant has demonstrated that the combination of at least (i) valerian, (ii) passionflower, (iii) rhodiola, and (iv) hawthorn has a synergistic effect to help the management of stress relaxation and / or falling asleep.

By synergistic effect, it is understood according to the present invention that the combination of at least (i) valerian, (ii) passionflower, (iii) rhodiola, and (iv) hawthorn has an effect on the aid in relaxation and / or sleep during treatment which is superior to the cumulative effects of a treatment (a) comprising the administration of valerian, not associated with passionflower, rhodiola and hawthorn, and conversely a treatment (b) comprising the administration of passionflower, not associated with valerian, rhodiola and hawthorn or a treatment (c) comprising the administration of rhodiola, not associated with valerian, hawthorn and passion flower or treatment (d) comprising the administration of hawthorn, not associated with valerian, passionflower and rhodiola. Valerian

Valerian Valerian or Valerian Hills or Valerian small leaves (Valeriana officinalis L.), also known under the vernacular names of Grass-au (x) -chat (s), Herb of Saint-Georges, or Bruised grass is a perennial herb of the family Valerianaceae. In the West its roots are traditionally used for their sedative and anxiolytic effects. They would promote sleep and reduce anxiety and are therefore considered a natural alternative to sleeping pills and chemical anxiolytics.

Passionflower Passiflora is a genus of plants, the passiflora, of more than 530 species of the family Passifloraceae. They are spectacular flowering climbers, but their abundance is only guaranteed in areas with mild climate.

The aerial parts of the officinal passionflower (Passiflora incarnata) are known in herbal medicine for their anxiolytic and sedative action. Indeed, Passiflora incarnata has several alkaloids including inhibitors of monoamine oxidase (MAOI) and light sedatives.

Rhodiola

The Pink Orpin, Rhodiola, Rhodiola, Golden Root or Arctic Root (Rhodiola rosea, synonym Lignum rhodium or Sedum roseum) is a plant species of the family Crassulaceae. It grows in cold regions such as the Arctic, the mountains of Central Asia, the Rocky Mountains, and the mountainous regions of Europe, such as the Alps, the Pyrenees, and the Carpathians, Scandinavia, Iceland, the Kingdom United Kingdom and Ireland. This perennial grows up to 2,280 meters above sea level.

Rhodiola rosea can improve depressive states. Pilot studies conducted on patients show improved physical and mental performance, and can reduce fatigue.

The hypothesis is that the effects of Rhodiola rosea would alter serotonin and dopamine levels through the inhibition of monoamine oxidase and its Opioid peptides, such as beta-endorphins, although these specific neurochemical mechanisms have not been clearly defined by scientific studies.

Rhodiola is classified as an adaptogen, which differs from stimulants such as nicotine and amphetamine. The adaptogenic factor has less efficacy and different physiological effects of the stimulants.

Extracts of Rhodiola rosea have an anti-fatigue effect that increases mental performance, especially concentration skills in healthy subjects and in burnout patients with fatigue syndrome. Rhodiola reduces fatigue symptoms and improves attention after four weeks of intake. hawthorn

The hawthorn used for pharmacological purposes are one-style hawthorn (Crataegus monogyna) and thorny hawthorn (Crataegus laevigata) (the latter being considered less effective). Both are commonly small trees of 2 to 4 meters, of the genus Crataegus and the Rosaceae family, very common in hedgerows of the European countryside. Their white flowers bloom in May.

In herbal medicine, hawthorn, or hawthorn flowers, are valued for their ability to regulate heart rhythm, improve coronary circulation and nutrition of the heart muscle. It is a hypotensive, cardiotonic and antispasmodic, which calms palpitations, reduces stress and facilitates sleep, thanks to flavonoids, sterols and triterpenes that contains the plant. Non-toxic, it could, in excessive doses, have a depressive action on the heart and affect the liver cell. It is therefore necessary to avoid prolonged cures and to cut them from rest intervals.

Physiologically acceptable medium

A physiologically acceptable medium is a medium having no toxic or detrimental effect under the conditions of use and inert with respect to the active ingredients of the combination product. Such a medium may, for example, comprise various adjuvants according to its therapeutic or cosmetic purpose, as in a nonlimiting manner, flavors, dyes, fillers, preservatives, diluents, wetting agents or suspension, etc. Such media may also allow immediate, modified or delayed release of either active ingredient.

The physiologically acceptable medium may be water, mash and / or fruit juice, texturizers, emulsifiers, colorants, preservatives, flavorings, sugar or sugars.

By "mash and / or fruit juice" is meant a more or less liquid preparation, in particular according to the nature of the fruit and / or the fineness of the grinding, prepared by grinding, pressing or other extraction process of one or several fruits and optionally the concentration of the ground material obtained and / or separation (in particular filtration) of the seeds, achenes and / or all or part of the pulp, and / or flash pasteurisation.

The fruits can be chosen from: apple, banana, strawberry, peach, raspberry, blackberry, mango, kiwi, blueberry, blackcurrant, currant, orange, cherry, fig, pear, apricot, coconut, passion fruit, guava, papaya, melon, lychee, pineapple, lemon, mandarin, mirabelle plum, grapefruit, grape, rhubarb and their mixtures, without this list being exhaustive.

"Texturizers" means compounds that modify the texture of the products in which they are incorporated. Examples of texturants are: guar and carob flour; gum arabic, xanthan and gellan; carrageenans; starches (native or modified); microcrystalline cellulose; gelatin; pectin; alginates (E400 to E405); agar-agar; and their mixtures. By "emulsifiers" is meant amphiphilic compounds characterized by their HLB (Hydrophilic Lipophilic Balance) value, in particular capable of stabilizing oil-in-water emulsions (particularly advantageous if it is desired to add, for example, liposoluble active agents such as Liposoluble vitamins Examples of food emulsifiers are lecithin and its derivatives present in particular in egg yolk, mono- and diglycerides of fatty acids, and polysorbate 80.

By "dyes" is meant compounds of natural or synthetic origin capable of conferring on their own a coloration to the composition. Examples of food colorants are known in Europe under the codes El 00 to El 80.

By "preservatives" is meant compounds inhibiting the proliferation of microorganisms, in particular yeasts and / or molds and / or bacteria, in particular Staphylococcus Aureus, in the composition. Examples of food preservatives are sorbic acid and its salts (E200 to E203: benzoic acid and its salts (E210 to E219), sulfites and derivatives (E220 to E228), natamycin, nisin, and mixtures thereof Preferably, the composition according to the invention does not comprise any preservative. "Aromas" means compounds of natural or synthetic origin which alone are capable of modifying the taste of the composition. apricot, pineapple, banana, blackcurrant, cherry, lemon, lime, strawberry, raspberry, passion fruit, mandarin, mint, orange, pistachio, pear, licorice, rose, anise, blueberry, cinnamon, ginger, grapefruit, apple, kiwi, lychee, melon, coconut, peach, currant, guava, grenadine, mango, blackberry, papaya, vanillin, natural vanilla extract, essential oils and their mixtures.

For the purposes of the present invention, sugar or sugar is understood to mean any sweetening carbohydrate, preferably glucose syrup, sucrose, glucose, fructose, invert sugar, honey, maltose, polyol or mixtures thereof. In the context of the present invention, the sugar used is a polyol, preferably sorbitol.

Additional asset (s)

Any additional active ingredient of nutritional interest and / or aiding in relaxation or asleep may also be added to the combination products of the invention in pharmaceutical or cosmetic form. The combination product may include, by way of example, vitamins, mineral salts, essential amino acids, essential fatty acids, trace elements, various plant extracts, fibers, antioxidants, flavonoids.

Advantageously, such additional asset may be intended to enhance the desired effect as described above. Of course, those skilled in the art will take care to choose the additional assets and their amount so that the advantageous properties of the composition according to the invention are not, or not substantially impaired by the addition envisaged.

As additional assets that can be used, mention may be made of: - water-soluble vitamins and fat-soluble vitamins. Examples of water-soluble vitamins present in the syrupy product prepared according to the invention are in particular: vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid) also called vitamin PP (preventive pellagra), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B8 or H (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin) and vitamin C (ascorbic acid). Examples of liposoluble vitamins present in the syrupy product prepared according to the invention are in particular: vitamin A (retinol), vitamin D3 (cholecalciferol), vitamin E (mixture of tocopherols and tocotrienols) and vitamin K (phylloquinone) . antioxidants, such as curcuminoids; carotenoids, especially chosen from beta.-carotene, astaxanthin, zeaxanthin, lutein or compounds containing them, such as goji berries; polyphenol compounds, flavonoids such as catechins; proanthocyanidins, anthocyanins, OPCs (procyanidolic oligomers); ubiquinones; coffee extracts containing polyphenols and / or diterpenes; chicory extracts; ginkgo biloba extracts; grape extracts rich in proanthocyanidins; chili extracts; soy extracts; Cocoa ; the grenade ; the Emblica; CoenzymeQ10; selenium,

minerals, such as zinc, calcium, copper, iron, iodine, manganese, selenium, chromium (III), amino acids, especially sulfur-containing amino acids, such as precursors of glutathione, the amino acids of selenium, citrulline,

phytosterols, resveratrol, hesperidin, neohesperidin, orthosilicic acid, monomethylsilanetriol, and mixtures thereof.

In a particularly advantageous embodiment of the invention, the combination of active agents comprises, as additional active ingredient, a fat-soluble vitamin, in particular vitamin D3, minerals such as potassium or magnesium.

Preferably, a combination product according to the invention is administered orally. Suitable forms for the oral route are, for example, tablets, capsules, lozenges, powders, granules, lyophilisates, oral solutes and syrups. Tablets, powders, granules, lyophilisers, drinkable solutions and syrups constitute the pharmaceutical or cosmetic form adapted to the currently preferred oral route. In the case of the preparation of a solid composition in the form of tablets, it is possible for example to mix the main active ingredients (i), (ii), (iii) or (iv) with a physiologically acceptable vehicle such as gelatin, starch, magnesium stearate, talc, gum arabic or analogies. The tablets may be varied in nature, immediate release, controlled or delayed and optionally in effervescent or orodispersible form.

A capsule preparation is obtained by mixing the active ingredient (i), (ii), (iii) or (iv) in powder form and pouring the resulting mixture into soft or hard gelatin capsules. Example of composition according to the invention (Table 1):

This composition is obtained by mixing the various compounds according to the methods conventionally used for this type of preparation. The composition is then preferably injected into capsules.

Claims

1. Combination product comprising as active substances at least:

(i) valerian,

(ii) passionflower,

(iii) rhodiola, and

(iv) hawthorn or a bioequivalent compound of valerian, passionflower, rhodiola or rhodiola to aid in stress management, relaxation and / or sleep.

2. Combination product according to one of claims 1 or 2, characterized in that it is in the form of a single composition containing at least:

(i) valerian,

(ii) passionflower,

(iii) rhodiola, and (iv) hawthorn in a physiologically acceptable medium.

3. Combination product according to one of the preceding claims characterized in that the physiologically acceptable medium is suitable for oral administration.

4. Combination product according to one of the preceding claims characterized in that it is in the form of a capsule comprising the active form of powder.

5. Combination product according to one of the preceding claims characterized in that valerian, passionflower, rhodiola and hawthorn are in the form of plant extracts

6. Combination product according to at least one of the preceding claims, for the treatment of subjects with somnipathy.